Process for the preparation of 17-substituted-delta4-gonenes and intermediates

ABSTRACT

A PROCESS FOR THE PRODUCTION OF A $4-GONENIC STEROID HAVING THE FORMULA   3-(O=),13-R,17-RIV,17-(R&#39;&#39;-O-)G0NA-4,9-DIENE   WHEREIN R REPRESENTS A MEMBER SELECTED FROM THE GROUP CONSISTING OF HYDROGEN AND THE ACYL OF AN ORGANIC CARBOXYLIC ACID HAVING FROM 1 TO 18 CARBON ATOMS, R&#39;&#39; REPRESENTS AN ALKYL HAVING FROM 1 TO 4 CARBON ATOMS, RIV REPRESENTS A MEMBER SELECTED FROM THE GROUP CONSISTING OF LOWER ALKYL, LOWER ALKENYL OR LOWER ALKYNYL, AND B REPRESENTS A MEMBER SELECTED FROM THE THE GROUP CONSISTING OF TWO HYDROGENS IN THE 9A AND 10B POSITION AND A DOUBLE BOND WHICH COMPRISES THE STEPS OF REACTING A 3-KETAL-4,5-SECO-GONANE-5-ONE WITH A KETALIZING AGENT, OXIDIZING THE RESULTANT 3,5-DIKETAL-4,5-SECO-GONANE-17B-OL, REACTING THE RESULTANT 3,5-DIKETAL-4,5-SECO-GONANE-17-ONE WITH AN ORGANOMETALLIC COMPOUND, HYDROLYZING THE RESULTANT 3,5-DIKETAL-17A-RIV-4,5-SECOGONANE-17B-OL, CYCLIZING THE RESULTANT 17A-RIV-4,5-SECO-GONANE-17B-OL-3,5-DIONE AND RECOVERING SAID $4-GONENIC STEROID. THE NOVEL INTERMEDIATES ARE ALSO PART OF THE INVENTION. THE $4-GONENIC STEROIDS ARE KNOWN COMPOUNDS HAVING STEROIDAL PROPERTIES.

United States Patent 3,702,334 PROCESS FOR THE PREPARATION OF 17-SUBSTI-TUTED-M-GONENES AND INTERMEDIATES Julien Warnant, 16 Place du Marche, 92Neuilly-sur-Seine,

France; Jean Jolly, Vallee des Anges C.D., 93 Clichysous-Bois, France;and Robert Joly, 8 Rue Chevalier, 95 Montmorency, France No Drawing.Filed Aug. 12, 1970, Ser. No. 63,277 Int. Cl. C07c 167/02 US. Cl.260-3974 3 Claims ABSTRACT OF THE DISCLOSURE A process for theproduction of a A gonenic steroid having the formula wherein Rrepresents a member selected from the group consisting of hydrogen andthe acyl of. an organic carboxylic acid having from 1 to 18 carbonatoms, R represents an alkyl having from 1 to 4- carbon atoms, Rrepresents a member selected from the group consisting of lower alkyl,lower alkenyl or lower alkynyl, and B represents a member selected fromthe group consisting of two hydrogens in the 90: and 10,3 position and adouble bond which comprises the steps of reacting a3-ketal-4,5-seco-gonane-5-one with a ketalizing agent, oxidizing theresultant 3,5-diketal-4,S-seco-gonane-175-0], reacting the resultant3,S-diketal-4,5-seco-gonane-17-one with an organometallic compound,hydrolyzing the resultant 3,5-diketal-l7a-R -4,5-secogonane-1718-01,cyclizing the resultant 17a-R -4,5-seco-gonane-17 8-ol-3,5-dione andrecovering said A -gonenic steroid. The novel intermediates are alsopart of the invention. The A -gonenic steroids are known compoundshaving steroidal properties.

REFERENCE TO PRIOR APPLICATIONS This application is acontinuation-in-part and a divission of the co-pending application Ser.No. 640,507, filed May 23, 1967, Pat. No. 3,591,606.

THE PRIOR ART It is a well known fact that the preparation of l9-norsteroids substituted in the 17-p0sition presents difiicult problems dueto the presence of the functions on the steroid molecule apt to beattacked at the very moment of the introduction of the desiredsubstituent in the 17- position. This is the case, in particular, withsteroids having a ketone function in the 3-position and/or double bondin the 4,5-position.

Moreover, it is known that in the former processes for the preparationof steroid derivatives by means of total synthesis, the authors have, asa rule, preferred to complete the construction of the steroid skeletonfirst, and only then to proceed with the substitution in the 17-p0siti0n(see, for example, Velluz et al., Recent Advances in the Total Synthesisof Steroids, Angew. Chem. Intern, Edit, vol. 4 [1965] No. 3).

OBJECTS OF THE INVENTION An object of the present invention is thedevelopment of a process to form a steroid substituted in the17-position from a steroid intermediate which can un- 4 3,702,334 IcePatented Nov. 7, 1972 wherein R represents a member selected from thegroup consisting of hydrogen and the acyl of an organic carboxylic acidhaving from 1 to 18 carbon atoms, R represents an alkyl having from 1 to4 carbon atoms, R rep resents a member selected from the groupconsisting of lower alkyl, lower alkenyl and lower alkynyl, and Brepresents a member selected from the group consisting of two hydrogensin the and l0fl-position and a double bond, which comprises (1) reactinga 4,5-seco-gonane-5- one of the formula wherein R and R have theabove-assigned meanings, Z is a member selected from the groupconsisting of oxygen,

ORII

wherein R-" is lower alkyl and R" is selected from the group consistingof lower alkylene and substituted lower alkylene, and A is selected fromthe group consisting of two hydrogens and a double bond, with aketalization agent under ketalizing conditions, (2) saponifying theresultant 3,5 diketals of 4,5 seco-gonane 3,5 diones of the formulawhere X is a member selected from the group consisting of OR" o and OR"0 wherein R" and R have the above-assigned meanings, R and A have theabove-assigned meanings, and R is the acyl of an organic carboxylic acidhaving from 1 to 18 carbon atoms, by the action of an alkalinesaponifying agent, (3) oxidizing the resultant 3,5 diketals of 4,5-seco-gonane-l7p-ol-3,5-diones of the formula wherein R, X and A have theabove-assigned meanings by the action of an hydroxyl oxidizing agent,(4) reacting the resultant 3,5 diketals of 4,5-seco-gonane-3,S,17-

triones of the formula wherein R, X and A have the above-assignedmeanings with an organometallic compound of the formula selected fromthe group consisting of R Li and R MgX, wherein R has the above-assignedmeaning and X represents halogen, (5) recovering the resultant3,5-diketals of 17a- R-4,5-seco-gonane-3,5-diones of the formula whereinR, R, R, X and A have the above-assigned meanings, (6) hydrolyzing saidcompounds by the action of a ketal hydrolyzing agent in the presence ofan organic solvent, (7) subjecting the resultant l7a-R-4,5-secogonane-3,5diones of the formula wherein R, R, R and A have theabove-assigned meanings to the action of a cyclizing agent selected fromthe group consisting of acid and basic cyclization agents, and (8)recovering said A gonenic steroid.

A further object of the present invention is the obtention of the novelintermediates: the 3,5 diketals of 170:- R 4,5 seco gonane 3,5 diones;and the flat-R"- 4,5-seco-gonane-3,5-diones.

These and other objects of the present invention will become moreapparent as the description thereof proceeds.

DESCRIPTION OF THE INVENTION medium an excellent stability with regardto the functions in the 3 and 5 positions, which facilitates thepossible conversions in the 17 position. Moreover, they are, aftersplitting OK the ketal functions in the 3 and 5 positions, easilycyclized by the usual agents to give the tetraacyclic steroid skeleton.

The present invention relates to a new class of intermediate productsfor the synthesis of steroid derivatives as well as to a process for thepreparation of these products.

More particularly, the invention relates to the 3,5- diketals of the13/8 alkyl 17a R 17B OR 4,5- seco-gonane-3,5-diones of the generalFormula I.

wherein, here and in the following, R represents hydrogen or the acyl ofan organic carboxylic acid having 1 to 18 carbon atoms, R is an alkylradical containing 1 to 4 carbon atoms, X represents the group ORII ORIIR" being a lower alkyl, or X represents the group wherein R, R' and R"have the above-assigned meanings. The process for the preparation of A-gonenic steroids of the general Formula III, also object of the presentinvention,

wherein R, R' and R have the above-assigned meanings and B is a doublebond or two hydrogens in the and 10;?! position, is characterized inthat a 3-Z-13fl-alkyl-l7fl- OR-4,5-seco-gonane-5-one of the generalFormula IV wherein X, R, R and the dashed line have the aboveassignedmeanings, when R represents the radical of an organic carboxylic acidhaving from 1 to 18 carbon atoms, is saponified, and the diketal of thegeneral Formula VI INT X vr wherein X, R and the dashed line have theabove-assigned meanings, is reacted with an oxidizing agent. Theresulting 3,5-diketal of 13 3-alkyl-4,5-seco-gonane-3,5,l7-trione of thegeneral Formula VII wherein R and X have the above-assigned meanings, isisolated.

The process, also object of the invention, can be advantageouslyexecuted as follows:

(A)The ketalization agent is chosen from the group consisting of thelower cyclic ketals, the lower non-cyclic ketals and the lower alkanols.The work is conducted in the presence of an acid catalyst.

(B) The cyclic ketals are chosen from the group consisting ofZ-methyl-2-ethyl-dioxolane, 2-methyl-2-phenyldioxolane,2-methyl-4-(6-methylbenzyl)-dioxolane, 2,2-dimethyl 4 (6methy1benzyl)-dioxolane, 2-chloromethy1 dioxolane, 2-(fi-chloro)-ethyl-dioxolane and 2-(B-bromo)- ethyl-dioxolane.

(C) The non-cyclic ketals are selected from the group consisting of thedimethyl ketal of acetone, the diethyl ketal of acetone, the dimethylketal of Z-butanone, the dimethyl ketal of dimethylformamide and thediethyl ketal of dimethylformamide.

(D) The aliphatic alcohols employed as ketalizing agents are chosen fromthe group consisting of glycols such as lower alkanediols, for example,ethyleneglycol, 1,3-propanediol, 2,2-dimethyl-1,3-propanediol, and oflower alkanols such as methanol or ethanol.

(E) The saponification of the 3,5-diketal of 13,3-alkyl-175-acy1oxy-4,5-seco-gonane-3,5-dione of the general formula V iseffected by an alkaline agent such as an alkali metal hydroxide, forexample, sodium or potassium hydroxide. The work is carried out in alower alkanol such as methanol or ethanol.

(F) The oxidation of the hydroxyl in the 17 position is realizedaccording to the Oppenauer method by means of a lower aliphatic ketonesuch as lower alkanones, for example, acetone, methylethyl ketone,methylisobutyl ketone or lower cycloalkanones, for example, cyclohex-VII 6 anone, in the presence of an aluminum tertiary lower alkanolatesuch as aluminum isopropylate.

(G) The oxidation of the hydroxyl in the 17 position is elfected byusing, as oxidizing agent, chromic acid anhydride in pyridine.

As it hasalready been mentioned, the advantages of the novel compoundsof the general Formula VII lie in particular in the fact that they allowan easy preparation of 19-nor steroids substituted in the 17 position,as it will be explained in the following.

The introduction of a substituent in the 17m position is realized, forexample, by reaction of a compound of Formula I with an organometalliccompound of the type R Li or R MgX (X being a halogen and, inparticular, bromine or iodine and R represents a hydrocarbon radical,preferably lower alkyl, lower alkenyl or lower alkynyl).

In the particular case of ethynylation, this reaction may be realizedwith the aid of an ethynyl magnesium halide or also with the aid of analkali metal acetylide or also with the aid of acetylene while operatingin the presence of tertiary alcoholates or amides of alkali metals oralkaline earth metals.

The introduction of the ethyl or vinyl radical in the 17a position canbe etfected with excellent yields in an indirect fashion in two steps.By ethynylation of the ketone in the 17 position and subsequentreduction of the ethynyl radical by hydrogenation in the presence of acatalyst having a platinum or palladium base, the 17methyl derivative isobtained, Whereas if the reduction is arrested after the absorption of amol equivalent of hydrogen gas, the t-VII1YI derivative is obtained.

The process of indirect introduction may furthermore be significant withregard to the preparation of the 17mpropyl derivatives. In that thecase, allyl magnesium bromide can be reacted with a compound of FormulaI, then the resultant allylic derivative is subjected to a hydrogenationin the presence of a catalyst having a platinum or palladium base.

The 3,5-diketals of the 13,8-alkyl-17a-R -17B-hydr0xy-4,5-seco-gonane-3,S-diones, possibly having a double bond in the 9(11)position (I, R=H), obtained by the above reactions, can be esterified inthe 17 position with an organic carboxylic acid having from 1 to 18carbon atoms by employing the usual acylation agents such as thecorresponding acid, its anhydride or its chloride.

Such acids are the aliphatic or cycloaliphatic carboxylic acids,saturated or unsaturated, or the aromatic or heterocyclic carboxylicacids, for example, the alkanoic acids such as formic, acetic,propionic, butyric, isobutyric, valeric, isovaleric, trimethylacetic,caproic, fl-trimethylpropionic, enanthio, capylic, pelargonic, capric,undecylic, lauric, myristic, palmitic, stearic, etc., the alkenoic acidssuch as undecylenic, oleic, etc., the cycloalkyl carboxylic acids suchas cyclopentyl-, cyclopropyl-, cyclobutyland cyclohexyl-carboxylicacids, the cycloalkylalkanoic acids such as cyclopropylmethyl carboxylicacid, cyclobutylmethyl carboxylic acid, cyclopentylethyl carboxylicacid, cyclohexylethyl carboxylic acid, the cyclopentylacetic,cyclohexylacetic, or propionic acids, the phenylalkanoic acids such asphenylaoetic or propionic acids, benzoic acid, the phenoxyalkanoic acidssuch as phenoxyacetic acids, p-chlorophenoxyacetic acid,2,4-dichlorophenoxyacetic acid, 4-tert.-butyl-phenoxyacetic acid,3-phenoxypropionic acid, 4-phenoxybutyric acid, the furane 2-carboxylicacids such as 5-tert.-butylfurane-Z-carboxylic acid,S-bromo-furane-2-carboxylic acid, the nicotinic acids, thep-ketoalkanoic acids, for example, the acetylacetic, propionylacetic,butyrylacetic acids, etc.

The 3,5-diketals of the l3B-R-17ot-R -17fl-hydroxy- 4,5 seco gonane 3,5diones with or without a 9(11) double bond, whether esterified orunesterified in the 17 3 position, can be subsequently converted intotertacyclic steroids.

For that purpose, such a 3,5-diketal of a 13fi-R'-17a- R -17fi-hydroxyor175 acyloxy 4,5 seco-gonane-3,5- dione formed as indicated above issubjected to a ketal hydrolysis in the presence of an acid, such ascitric, acetic, hydrochloric or sulfuric acid, and in the presence ofone or several solvents such as an alcohol, for example, the methanol orethanol, and a hydrocarbon such as benzene or toluene. In this mannerthe ketone in the 3 and 5 positions are regenerated and thecorresponding 3,5-dioxo derivative is recovered possibly having a doublebond in the 9(10) position. Next, this 3,5-dioxo derivative is subjectedto the action of a basic cyclization agent such as an alkali metalalcoholate, or to the action of an acid cyclization agent such ashydrochloric acid or the hydrochloric acid-acetic acid mixture.

Thus, a tetracyclic steroid of the general Formula III III wherein R, Rand R have the previous meanings, is obtained possibly with a doublebond in the 9(10) position.

In the case where the cyclization agent is a secondary base such as, forexample, pyrrolidine, the corresponding enamines are obtained in the3-position, which by means of acid hydrolysis supply the above-indicated3-oxo-A or El-oxo-A derivatives.

By applying the methods described in the preceding, it is possible toprepare, starting with the compounds of the general Formula I,physiologically active steroids such as, for example,17m-ethynyl-19-nor-testosterone, 17ccethyl-l9-nor-testosterone, theacetate of 17a-ethynyl-19-nor-testosterone, 17a-ethynyl-A-estradiene-17B-ol-3-one, 13fl-ethyl-17u-ethynyl-A-gonene-17fl-ol-3-one, 133,17a-diethyl-A -gonene-l7/3-ol-3-one,13B-ethyl- 17u-ethynyl-A -gonadiene-175-01-3-one and the corresponding13fl-n-propyl and 13B-n-buty1 derivatives.

As it has been shown in the preceding, tetracyclic steroids of gonanicstructure can be prepared by starting with the compounds of Formula IV.

The starting compounds of the process of the invention are described andare accessible by application of the processes of French Patents Nos.1,243,000, 1,364,556, 1,476,509 and 1,432,569.

The following examples will serve for better comprehension of theinvention. However, it is to be understood that they are not to bedeemed limitative in any degree. The process described in the followingcan also be applied with the same readiness to the 135-ethyl, 13B-propyl or 135-butyl derivatives as to the 13,8-methyl derivatives.

EXAMPLE I Preparation of 3-ethylenedioxy-4,5-seco-estrane- 17/3-ol-5-one900 cc. of toluene, 18 cc. of pyridine, 180 gm. of 3- ethylenedioxy 4,5seco-A -estrene-17fl-ol-5-one and 72 gm. of palladized talc containing2% of palladium, were introduced into a hydrogenation vessel. The vesselwas purged and the mixture was agitated under an atmosphere of hydrogenat room temperature. Over a period of 6 hours about 12 liters ofhydrogen were absorbed.

Thereafter, the reaction solution was filtered and 180 cc. of water wereadded thereto. Next, the Washing was effected, followed by decanting,first with an aqueous solution of normal sulfuric acid to eliminate thepyridine, then with an aqueous solution of sodium bicarbonate andfinally with water until the wash waters were neutral. The toluene phasewas dried over magnesium sulfate, concentrated to dryness under reducedpressure, thus obtaining 180 gm. of raw3-ethylenedioxy-4,5-seco-estrane- 17;.8-ol-5-one. This product was usedas such for the next step.

A sample of this product was purified for analysis by recrystallizationfrom isopropyl ether containing 1 part per thousand of pyridine, thenfrom ethyl ether containing 1 part per thousand of pyridine. It had amelting point of to C. and a specific rotation [a] =+3i1 (c.=1% inmethanol containing 1% of pyridine), and it possessed the followingcharacteristics:

Analysis.-C H O molecular weight=336.46. Calculated (percent): C, 71.39;H, 9.59. Found (percent): C, 71.2; H, 9.5.

Infrared spectra (in chloroform).Absorption at: 1,704 cm.- carbonyl;3,600 cmr' z hydroxyl and CO-C band, characteristic of the ketalfunction.

This product is not described in the literature.

The 3 ethylenedioxy-4,5-seco-A -estrene-17fi-ol-5-one, utilized as thestarting product in the preceding preparation, was obtained in thecourse of the process described in French Pat. No. 1,364,556.

In an analogous manner, the 3-ethylenedioxy-l3fi-ethyl-4,5-seco-gonane-17fi-ol-5-one was prepared by starting with the3-ethylenedioxy-13 8-ethy1-4,5-seco A gonene- 17B-ol-5-one, having amelting point of to C., this product being obtained in the course of theprocess described in the French Pat. No. 1,476,509. TheS-ethylenedioxy-l3fi-ethyl-4,5-seco-gonane-17fl-o1-5-one is notdescribed in the literature.

EXAMPLE II Preparation of 3,5 -bis- (ethylenedioxy4,5-seco-estrane-17-one Step A: Preparation of3,5-bis-(ethylenedioxy)-4,5- seco-estrane-17 8-ol.Under an inertatmosphere, first 70 gm. of3-ethylenedioxy-4,5-seco-estrane-17,8-ol-5-one, then 0.35 gm. ofparatoluene sulfonic acid were introduced into 350 cc. ofmethylethyldioxolane. The mixture was agitated for about 15 hours.Thereafter, the reaction mixture was made alkaline with 2.1 cc. ofpyridine, agitated for 10 minutes, then 126 cc. of water and 14 cc. of asaturated aqueous solution of sodium bicarbonate was added. The organicphase was separated by decanting and washed with water. The aqueous washwaters were extracted with benzene, which was washed with water, thencombined with the organic phase previously isolated and washed. Thesecombined organic phases were dried over magnesium sulfate andconcentrated to dryness under reduced pressure. The residue was taken upin isopropyl ether and concentrated to dryness under reduced pressure.84 gm. of a raw product were recovered, which was crystallized fromisopropyl ether, obtaining 69.7 gm. of3,5-bis-(ethylenedioxy)-4,5-seco-estrane-17B-ol.

The product had a specific rotation [a] =+18i1 (c.=1% in methanolcontaining 1% of pyridine).

By concentration of the mother liquors resulting from thecrystallization, a second yield of product was obtained.

A sample of the product was purified for analysis from isopropyl ethercontaining 1 part per thousand of pyridine. It had a melting point of 90to 100 C. and a specific rotation [a] =+19i1 (c.=1% in methanolcontaining 1% of pyridine), and possessed the following characteristics:

Analysis.--C H O molecular weight=380.50. Calculated (percent): C,69.44; H, 9.53. Found (percent): C, 69.1; H, 9.7.

Infrared spectra (in chloroform).-Absorption at 3,600 cmr' z hydroxyland CO-C band characteristic of the ketal function.

This product is not described in the literature.

Step B: Preparation of 3,5-bis-(ethylenedioxy)-4,5- secoestrane-17-one.Under an inert atmosphere, 40 gm. of purified3,5-bis-(ethylenedioxy)-4,5-seco-estrane- 1718-01 were dissolved in amixture of 400 cc. of toluene and 80 cc. of methylethylketone in a2-liter vessel equipped with an agitation means and a descendingcondenser. The solution was brought to boiling point under agitation.Then after distillation had been established, a solution of 14.4 gm. ofaluminum isopropylate in 540 cc. of toluene and 720 cc. ofmethylethyl-ketone was introduced. This addition was effected asfollows: The two reactants were introduced simultaneously at regularintervals for about 15 minutes and within a total time of 4 to 5 hoursin such a manner that the evaporated solvent volume was proportionatelycompensated by the addition of the two reactants. Thus, within a spaceof about 4 to 5 hours, 1,260 cc. of distillate were recovered. Thedistillation was continued until 80 cc. of distillate were recovered.The reaction mixture was cooled. Next, 36 cc. of water were introducedand the solution was agitated. The precipitated alumina was vacuumfiltered. Water was added to the filtrate and the organic solvents wereeliminated by steam distillation. The aqueous mixture was cooled and theprecipitate formed was vacuum filtered, washed with water and dried. Therecovered raw product was crystallized from methanol containing 1 partper thousand of pyridine, thus obtaining 30.8 gm. of 3,5-bis-(ethylenedioxy)-4,5-seco-estrane-17-one. The product had a melting pointof 114 C.

A sample of this product, purified for analysis by crystallization firstfrom isopropyl ether containing 1 part per thousand of pyridine, thenfrom methanol containing 1 part per thousand of pyridine, had a meltingpoint of 114 C. and a specific rotation [a] =-+75i1.5 (c.=l% in methanolcontaining 1% of pyridine), and had the following characteristics:

Analysis.C H O molecular weight=378.49. Calculated (percent): C, 69.81;H, 9.05. Found (percent): C, 69.9; H, 8.9.

Infrared spectra (in chloroform).Absorption at 1,732 cmr z carbonyl andC-O-C band characteristic of the ketal function.

This product is not described in the literature.

EXAMPLE HI Preparation of 3,5-bis-(ethylenedioxy)-4,5-seco-estrane-17-one, starting with 4,5-seco-estrane-l7p-ol-3,5-dione 10 gm. of4,5-seco-estrane-1713-01-3,5-dione, a product described in French Pat.No. 1,432,569, were introduced into 60 cc. of methylethyldioxolane. Themixture was brought to refiux under an inert atmosphere and 1 volume ofsolvent was distilled therefrom under normal pressure. The mixture wasthen cooled toward 75 C. and 0.050 gm. of paratoluene sulfonic acid wasadded. Under a slight vacuum, the mixture was distilled for 3 hours atabout 75 C., recovering about 10 cc. of distillate per hour andmaintaining the reaction media at a constant volume by the addition ofmethylethyldioxolane. Thereafter, the methylethyldioxolane waseliminated under reduced pressure. The reaction media was cooled. 20 cc.of benzene and 0.4 cc. of pyridine were added to the reaction mixture,which was then homogenized and was, after 18 cc. of water and 2 cc. of asaturated solution of sodium bicarbonate had been added, agitated for 10minutes. The benzenic phase was separated by decanting and washed withwater. The aqueous phases were re-extracted with benzene. After havingbeen washed with water, these benzenic re-extracts were combined withthe principal benzenic solution. After the addition of one drop ofpyridine, the whole of the combined benzenic solutions was concentratedto dryness under reduced pressure. The resultant residue was dissolvedin hot ethyl ether. The ether was expelled under vacuum and thecrystallizate was dried.

10 13.27 gm. of a raw product were obtained, having a melting point ofto C. and a specific rotation (c.=l% in methanol containing 1% ofpyridine).

This raw product was recrystallized from isopropyl ether containing 1part per thousand of pyridine, thus obtaining 8.75 gm. of3,5-bis-(ethylenedioxy)-4,5-seco-estrane-17,8- 01, having a meltingpoint of 90 C. to 100 C. with a specific rotation of [u] =+19.5 i1(c.=l% in methanol containing 1% of pyridine). This product wasidentical to the 3,S-bis-(ethylenedioxy)-4,5-seco-estrane-176-01prepared in Step A of the preceding example. By applyinging the processdescribed in Step B of the preceding example to this compound,3,5-bis-(ethylenedioxy)-4,5-secoestrane-l7-one was obtained, which wasidentical to the product prepared according to Example II.

EXAMPLE 1V Preparation of 3,5-bis-(ethylenedioxy)-4,5-seco-Aestrene-17-one Step A: Preparation of 3,5-bis-(ethylenedioxy)-17 8-benzoyloxy-4,5-seco-A -estrene.Under an atomsphere of nitrogen, 2gm. of17 3benzoyloxy-4,5-seco-A -estrene-3, S-dione, having a specificrotation [111 +43 (c.=l% in methanol), a product described in French'Pat. No. 1,243,000, were introduced into 60 cc. of methethyldioxolane.0.06 gm. of paratoluene sulfonic acid monohydrate were added thereto,and the reaction mixture was heated under agitation in order to obtainwithin the space of 5 hours a volume of distillate of about 20 cc. whilemaintaining the reaction volume constant by the regular addition ofmethylethyldioxolane. The pH was adjusted to 8.0 by the addition of anaqueous solution of sodium bicarbonate. The organic phase was separatedby decanting, washed with water until neutrality was attained and dried.One drop of pyridine was added to the organic phase, which was thendistilled to dryness under reduced pressure. Next, ethanol was added tothe residue and the mixture was again concentrated to dryness underreduced pressure.

The resultant residue was crystallized from ethanol, thus obtaining 1.6gm. of 3,5-'bis-(ethylenedioxy)-17p-benzoyloxy-4,5-seco-A -estrene. Theproduct had a melting point of 165 to 166 C.

A sample of this product, recrystallized first from isopropyl ether inthe presence of pyridine, then from ethanol also in the presence ofpyridine, had the following constants: Melting point=166 to 167 C.Specific rotation=[a] =+23.2 (c.=0.9% in methanol).

Analysis.C H O molecular weight=482.6. Ca1- culated (percent): C, 72.17;H, 7.93. Found (percent): C, 72.4; H, 8.1.

Ultraviolet spectra (in ethanol): max. at 230 mp, e=14,300; max. at 273mu, e=910; max at 280 mg, 5:720.

This product is not described in the literature.

Step B: Preparation of 3,5-bis-(ethylenedioxy)-4,5-seco- A-estrene-17/8-ol.Under an atomsphere of nitrogen, 600 mg. of3,5-bis-(ethylenedioxy)-17 9-benzoyloxy-4,5- seco-A -estrene wereintroduced into 19 cc. of a 0.158 N potassium hydroxide solution. Themixture was maintained at reflux for one hour, then concentrated todryness under reduced pressure. Next, water was added to the mixture,which was then extracted with ether and the extracts were combined. Theorganic solution obtained was washed with water, dried and concentratedto dryness. After adding isopropyl ether, the solution was crystallized,vacuum filtered and dried. In this manner, 36-2 mg. of 3,5-bis-(ethylenedioxy)-4,5-seco-A -estrene-17 8-01 were obtained having amelting point of C.

A sample of this product was purified by crystallization first fromisopropyl ether, then from petroleum ether (boiling range=60 to 80 C.).The product had a melting 1 1 point of 132 C. and a specific rotation[u] =+25.8 (c.=0.7% in methanol).

Analysis.-C H O molecular weight=378.49. Calculated (percent): C, 69.81;H, 9.05. Found (percent): C, 69.8; H, 9.1.

This product is not described in the literature.

Step C: Preparation of 3,5-bis-(ethylenedioxy)4,5-seco- A-estrene-17-one.Within a space of 10 minutes, about 1 gm. of chromicacid, followed by a solution composed of 10 cc. of pyridine and 1 gm. of3,5-bis-(ethylenedioxy)-4,5-seco-A -estrene-175-01 were introduced into10 cc. of pyridine cooled to C. This mixture was allowed to warm to atemperature of 20 C., then agitated for 15 hours at this temperature.Thereafter, the reaction mixture was poured into water and filtered. Theaqueous phase was extracted with methylene chloride and the methylenechloride extracts were combined. The organic solution obtained waswashed with water and dried, then concentrated to dryness under reducedpressure.

The residue was crystallized from isopropyl ether and 0.665 gm. of3,5-bis-(ethylenedioxy)-4,5 seco A estrene-17-one was obtained, having amelting point of 98 C.

A sample of this product was purified for analysis by crystallizationfrom isopropyl ether. It had a melting point of 98 C. and a specificrotation [a] =-+105 (0. =0.5% in methanol).

Analysis.-C H O molecular weight=376.46. Calculated (percent): C, 70.18;H, 8.56. Found (percent): C, 70.1; H, 8.5.

This product is not described in the literature.

EXAMPLE V Preparation of 17a-ethynyl-19-nor-testosterone Step A:Preparation of 3,5-bis-(ethylenedioxy)-17a-ethynyl-4,5-seco-estrane-17fi-ol.-Under agitation, astream of acetylene was allowed to bubble through 40 cc. of a sodiumtert.-amylate solution in toluene containing 2.28 gm. of sodium per 100cc. for 2 hours. Thereafter, 5 gm. of 3,5 bis (ethylenedioxy) 4,5 secoestrane 17 one (described in Step B of Example II) and cc. of toluenewere introduced into the solution of sodium acetylide obtained. Themixture was then agitated for 3 hours and 30 minutes at room temperaturewhile a stream of acetylene was bubbled therethrough. Next, the reactionmixture was cooled to about C. under an inert atmosphere. A solution of5 gm. of ammonium chloride in 15 cc. of water was introduced. Thetoluene was distilled under reduced pressure while maintaining thevolume constant by addition of water, thus obtaining 5.28 gm. of3,5-bis-(ethylenedioxy)-17ot-ethynyl-4,S-seco-estrane-175-01. Theproduct had a melting point of 181 to 182 C. and was utilized as suchfor the next step.

A sample of this product, purified for analysis by recrystallizationfrom methanol containing 1 part per thousand of pyridine, had a meltingpoint of 183 C. and a specific rotation [oc] =30 22 (c.=1% in methanolcontaining 1% of pyridine) and possessed the following characteristics:

Analysis.-C H O molecular weight=404.52. Ca1- culated (percent): C,71.25; H, 8.97. Found (percent): C, 71.4; H, 9.0.

Infrared spectra (in chloroform).-Absorption at: 3,300 cm. ethynyl;3,590 cm.- hydroxyl and band characteristics of the ketal function.

This product is not described in the literature.

Step B: Preparation of 17a-ethynyl-4,5-seco-estrane-17B-ol-3,5-dione.-First, 1.5 gm. of 3,5-bis-(ethylenedioxy)-17a-ethynyl-4,S-seco-estrane-173-01, then 1.5 gm. of citric acid wereintroduced into a mixture of 7.5 cc. of toluene, 3 cc. of methanol and 3cc. of water. Under agitation and an inert atmosphere, the mixture washeld at reflux for one hour. Then 15 cc. of water were added thereto.The toluene was concentrated under reduced pressure. The precipitateformed was isolated by being vacuum filtered, washed with water untilthe wash waters were neutral and dried. Thus, 1.13 gm. of17ot-ethynyl-4,S-seco-estrane-17,B-ol-3,5- dione were obtained. Theproduct had a melting point of 135 to 136 C. and it was utilized as suchfor the following step.

A sample of this product, purified for for analysis by crystallizationfrom ethyl ether, had a melting point of 135 to 136 C. and a specificrotation [oc] =-50.4 :2 (c.=1% in methanol) and had the followingcharacteristics:

Analysis.'C- H O molecular weight =316.42. Calculated (percent): C,75.91; H, 8.91. Found (percent): C, 76.0; H, 8.9.

Infrared spectra (in chloroform) .Absorption at: 1,703 cmr z carbonyl;3,300 cmr ethynyl; 3,590 cmr z hydroxyl.

This product is not described in the literature.

Step C: Obtention of 17a-ethynyl-19-nor-testosterone.--Under an inertatmosphere, 0.900 gm. of 17a-ethynyl 4,5 seco-estrane-17fi-ol-3,5-dionewere introduced into a mixture of 9 cc. of methanol and 2.7 cc. ofmethylene chloride. The mixture was agitated for 15 minutes; then 1 cc.of a methanolic solution of sodium methylate, containing 7.8 gm. ofsodium per cc., was added, and the reaction mixture was agiated for 5hours at room temperature. Thereafter, 0.3 cc. of acetic acid and 10 cc.of water were added. Next, the methanol and the methylene chloride wereeliminated under reduced pressure, and the precipitate was vacuumfiltered. In this way, 0.84 gm. of 17a-ethynyl-19-nor-testosterone wereobtained. The product had a melting point of 206 C. and a specificrotation [a] =--22.5 (c.=2% in chloroform).

After having been purified, a sample of this product had a melting pointof 206.5 to 207 C. and a specific rotation [a] =--24i2 (c.=1% inchloroform) and was found to be identical to a sample of17a-ethynyl-l9-nortestosterone prepared according to a different method.

EXAMPLE VI Preparation of 17a-ethyl-19-nor-testosterone Step A:Preparation of3,5-bis-(ethylenedioxy)-17aethyl-4,5-seco-estrane-17/3-ol.-30 cc. oftoluene and 15 cc. of ethanol containing 0.2% of pyridine wereintroduced into a hydrogenation vessel, then 3 gm. of3,5-bis-(ethylenedioxy)-17wethylene-4,5-seco-estrane-17,8-01 describedin Step A of Example V) and finally 1.2 gm. of palladized talccontaining 2% of palladium were added. The apparatus was purged, and themixture therein was agitated under an atmosphere of hydrogen until thecompletion of absorption of the latter. Thereafter the reaction mixturewas maintained under agitation for 15 minutes and then the reactionsuspension was filtered. The filtrate was distilled to dryness underreduced pressure, obtaining 3.22 gm. of raw3,5-bis-(ethylenedioxy)-17a-ethyl-4,5-secoestrane-17301 which productwas utilized as such for the next step.

This product is not described in the literature.

Step B: Preparation of 17a-ethyl-4,5-seco-estrane-175-ol-3,5-dione.-2.l3 gm. of raw 3,5-bis(ethylenedioxy)-17a-ethyl-4,5-seco-estrane-175-01 were dissolved in a mixture of 10.7cc. of toluene, 4.3 cc. of methanol and 4.3 cc. of water. The solutionwas heated to reflux and 2.13 gm. of citric acid monohydrate were added.Then the solution was maintained at reflux for one hour; thereafter 10.7cc. of water were added. Next, the solution was concentrated underreduced pressure in order to eliminate the toluene and the methanol. Theproduct obtained was extracted with methylene chloride. The methylenechloride solution was dried over magnesium sulfate, distilled to drynessunder vacuum, thereby obtaining 1.55 gm. of raw 17a- 1 3ethyl-4,5-seco-estrane-l75-01-3,S-dione, which was utilized as such forthe next step.

Infrared spectra ,(in chloroform).Absorption at: 1,358 cmr z (f-CH;

1,708 cm.- carbonyl; 3,600 cmr z hydroxyl.

This product is not described in the literature.

Step C: Obtention of 17a-ethyl-19-nor-testosterone.- 1.35 gm. of 17aethyl-4,5-seco-estrane-17fl-ol-3,5-dione were dissolved in 7 cc. ofmethanol, and 0.236 gm. of sodium methylate were added thereto. Next,the solution was agitated for 5 hours at room temperature and thereafterneutralized by the addition of acetic acid. The methanol was distilledtherefrom under reduced pressure. Water was added and the insolubleportion of the reaction mixture was extracted with methylene chloride.The methylene chloride solution was dried over magnesium sulfate andconcentrated to dryness under reduced pressure. The resultant residuewas purified by trituration with ethyl ether, and 0.557 gm. of17a-ethyl-19-nor-testosterone was obtained. The product had a meltingpoint of 136 C. and a specific rotation of [0c] =-|-21i0.5 (c.=2% inmethanol).

Ultraviolet spectra (in ethanol): max. at 240 to 241 my, e=16,450.

This product was identical to 17a-ethyl-19-nortestossternone preparedaccording to a different method.

EXAMPLE VII Preparation of the acetate of l7a-ethynyl-l9-norestosteroneStep A: Preparation of 3,5 bis (ethylenedioxy)-17aethynyl175-acetoxy-4,5-seco-estrane.4 gm. of 3,5-bis- (ethylenedioxy)17a-ethynyl-4,5-seco-estrane-175-01 (described in Step A of Example V)were introduced into a mixture of 8 cc. of pyridine and 4 cc. of aceticacid anhydride and heated at 100 to 105 C. for 24 hours. Thereafter, thereaction solution was poured into a water-ice mixture. The precipitateformed was vacuum filtered, washed with water and dried. This rawproduct was purified by trituration with methanol. The product obtainedafter purification with methanol was dissolved in methylene chloride andagitated with magnesium silicate. The methylene chloride solution wasfiltered and concentrated to dryness under reduced pressure, therebyobtaining 3.53 gm. of 3,5-bis-(ethylenedioxy)-l7a-ethynyl-17B-acetoxy-4,5-seco-estrane. The product had a melting point of 174 C. and wasutilized as such for the next step.

A sample of this product, purified for analysis by crystallization frommethanol, had a melting point of 174 C. and a specific rotation [a]='31.5i1 ,(c.=1% in chloroform containing 1% of pyridine) and possessedthe following characteristics:

Analysis.-C H O molecular weight=446.5 6. Calculated (percent): C,69.92; H, 8.59. Found (percent): C, 69.9; H, 8.8.

Infrared spectra (in chloroform).-Absorption at: 1,738 cm.- carbonyl;3,300 cmr z ethynyl.

This product is not described in the literature.

Step B: Preparation of 17a ethynyl-17fl-acetoxy-4,5- secoestrane-3,5-dione.-3.2 gm. of 3,5-bis-(ethylenedioxy)17a-ethynyl-17fl-acetoxy-4,5-seco-estrane were introduced into a mixtureof 16 cc. of toluene, 6.4 cc. of methanol and 6.4 cc. of water. Then thereaction mixture was heated to reflux, 3.2 gm. of citric acidmonohydrate were added, and the reaction mixture was maintained atreflux for 15 hours. Thereafter, 16 cc. of water were added to thereaction mixture, which was then distilled under reduced pressure inorder to eliminate the toluene and the methanol. After the precipitateobtained had been vacuum filtered and dried, 2.58 gm. of a product wererecovered which, after crystallization from methanol, supplied 2.2

14 gm. of 17a ethynyl 175 acetoxy-4,5-seco-estrane-3,5- dione. Theproduct had a melting point of 170 C. and it was utilized as such forthe next step.

A sample of this product, purified for analysis by crystallization frommethanol, had a melting point of 170 C. and a specific rotation of [a]=58 (c.=1% in chlorofrom) and showed the following characteristics:

Analysis.C H 0 molecular weight=35 8.46. Calculated (percent): C, 73.71;H, 8.43. Found ,(percent): C, 73.4; H, 8.3.

Infrared spectra (in chloroform).--Absorption at: 1,708 cmf carbonyl;1,738 curtcarbonyl of the acetate; 3,300 cm.- ethynyl.

This product is not described in the literature.

Step C: Preparation of the 3-pyrrolidyl-17a-ethynyl- 17B-acetoxy-A-estradiene.-0.500 gm. of l7a-ethynyl-17fl-acetoxy-4,5-scco-estrane-3,5-dione were introduced into 5 cc. ofmethanol; then 0.25 cc. of pyrrolidine were added. The mixture wasagitated for 15 hours at room temperature and under an atmosphere ofnitrogen. The precipitate formed was vacuum filtered and washed withmethanol, thus obtaining 0.52 gm. of3-pyrrolidyl-17aethynyl-17fi-acetoxy-A -estradiene. The product had amelting point of 186 C. and a specific rotation (c.=0.5% indimethylformamide). It was utilized as such for the next step.

Analysis.-C H O N; molecular weight=393.55. Calculated (percent): C,79.34; H, 8.96; N, 3.56. Found (percent): C, 79.1; H, 9.2; N, 3.9.

This product is not described in the literature.

Step D: Preparation of the acetate of 17a-ethynyl-19-nor-testosterone.-0.285 gm. of 3-pyrrolidyl-17a-ethynyl- 17fi-acetoxy-A-estradiene were introduced into 1.4 cc. of 2 N sulfuric acid. Themixture was agitated for 15 hours at room temperature; then it wasslowly poured into a mixture of 2.8 cc. of 2 N sodium hydroxide solutionand 5.7 gm. of water and ice. Next, the reaction mixture was againagitated for 2 hours at 0 C., acidified with 9 N sulfuric acid to obtaina pH of 1, and then again agitated for one hour at 0 C. The precipitateformed was vacuum filtered, washed with water and dried. This productwas twice recrystallized from a water-acetone mixture. 0.154 gm. ofacetate of 17u-ethynyl-19-nor-testosterone was obtained. The product hada melting point of 163 C. and a specific rotation [a] =-28.5 i-1%(c.-=1% in chloroform). It was identical to a sample of the acetate of17aethynyl-19-nor-testosterone prepared according to a differentprocess.

EXAMPLE VIII Preparation of l7a-ethynyl-A -estradiene-1713-ol-3-one StepA: Preparation of 3,5-bis-(ethylenedioxy)-17aethynyl-4,5-seco-A-estrene-17;8-ol.--Under an atmosphere of nitrogen, 2.6 gm. of potassiumwere introduced into a mixture of 26.4 cc. of tert.-amyl alcohol and10.4 cc. of benzene. The mixture was heated to 55 C. to 60 C. andmaintained at this temperature for one hour while agitating. Then astream of acetylene was allowed to bubble through the reaction solutionfor one hour and 30 minutes at a temperature of 55 to 60 C. Thereafter,the reaction solution was cooled to room temperature and, whilemaintaining the bubbling of acetylene therethrough, a solution of 500mg. of 3,5-bis(ethylenedioxy)-4,5-seco- A -estrene-l7-one (described inStep C of Example IV) in a mixture of 10.4 cc. of benzene and 10.4 cc.of ethyl ether was introduced into the reaction solution. The reactionmixture was then agitated for two hours while acetylene continued to bebubbled therethrough. Next, water was added to the reaction mixture. Theorganic phase was separated by decanting, washed with water, dried andconcentrated to dryness under reduced pressure.

The residue was triturated with isopropyl ether and then crystallizedfrom the same solvent. In this manner 350 mg. of3,5-bis(ethylenedioxy)-17a-ethynyl-4,5-seco- A9 -estrene-17 3-ol wereobtained, having a melting point of 152 C.

A sample of this product was purified for analysis by crystallizationfirst from isopropyl ether, then from aqueous methanol. The product hada melting point of 152 C. with a specific rotation [a] =-21.5 (c.=0.5%in methanol).

Analysis.C H O molecular weight=402.5l. Calculated (percent): C, 71.61;H, 8.51. Found: C, 71.5; H, 8.4.

This product is not described in the literature.

Step B: Preparation of l7u-ethynyl-4,5-seco-A-estrenel7fl-ol-3,5-dione.- Under an atmosphere of nitrogen, 6 gm. of3,5 bis (ethylenedioxy) 17a-ethynyl-4,5-seco- A -estrene-17p-ol wereintroduced into a mixture of 30 cc. of toluene and 12 cc. of methanol.Then 12 cc. of water were added to the mixture, which was then broughtto reflux while agitating. 6 gm. of citric acid were added and thereaction mixture was maintained at reflux for one hour. Thereafter, 30cc. of water were added and the methanol and toluene were eliminatedunder reduced pressure. The aqueous phase was extracted with methylenechloride. The extracts were combined and the organic solution obtainedwas washed with water, dried and finally concentrated to dryness underreduced pressure.

The residue was admixed with ether. The precipitate formed was isolatedby being vacuum filtered, and the mother liquors, which will be referredto hereinafter as Solution A, were preserved. The product obtained waspurified by crystallization from ether and 0.99 gm. of17aethynyl-4,5-seco-A -estrene-17fi-ol-3,5-dione was obtained having amelting point of 124 C.

A same of this product was recrystallized from ether and had a meltingpoint of 124 C. with a specific rotation [u] =-73 (c.=0.65% inmethanol).

Analysis.-C H O molecular weight=3l4.4l. Calculated (percent): C, 76.40;H, 8.33. Found (percent): C, 76.2; H, 8.4.

Ultraviolet spectra (in ethanol): A at 248 to 249 mp e=15,000.

This product is not described in the literature.

Moreover, by starting with the Solution A maintained at C. for severalhours, a precipitate was obtained. This precipitate was vacuum filteredand purified by crystallization from ethyl ether. In this manner, 210mg. of 17 ethynyl 4,5-seco-A -estrene-175-01-35- dione were obtained.The product had a melting point of 143 C. and a specific rotation [a]=-15 (c.=0.55% in methanol).

Analysis.--C H O molecular weight=3l4.4l. Calculated (percent): C,76.40; H, 8.33. Found (percent): C, 76.4; H, 8.2.

By employing the conventional processes of ketalization, this compoundwas converted into 3,5-bis-(ethylenedioxy) l7a-ethynyl-4,5-seco-A-estrene-175-01, which could be utilized again.

This product is not described in the literature.

Step C: Preparation of l7a-ethynyl-M estradiene-175- ol-3-one.-Under aninert atmosphere, 0.600 gm. of 17aethynyl 4,5-seco-A -estrene-l73-ol3,5-dione were introduced into 2.2 cc. of benzene. Then, whilemaintaining the temperature between 0 C. and +3" C., 1.4 cc. of asolution of sodium tert.-amylate in toluene, containing 2.45 gm. ofsodium per 100 cc., was added in the space of 20 minutes. Whilemaintaining the previously recited temperature, the reaction mixture wasagitated for 2 hours. Thereafter, first 1 cc. of benzene, then a mixtureof 0.3 cc. of tert.-butyl alcohol and 0.5 cc. of benzene were added tothe reaction mixture. The temperature was elevated to 20 C. and thereaction mixture was agitated for one hour at this temperature. The pHwas adjusted to 7 by the addition of a benzenic solution of acetic acid.Next, the reaction mixture was agitated for 45 minutes and then waterwas added. The solvents were eliminated under re- 1 6 duced pressure.The precipitate formed was vacuum filtered, washed and dried. 570 mg. ofproduct were obtained, having a melting point of 178 C.

This product was purified by crystallization from ethyl acetate, thusobtaining 416 mg. of l7aethynyl-A -estradiene-17/8-ol-3-one. The producthad a melting point of 183 C. and a specific rotation [a] =355 (c.=0.2%in methanol).

Ultraviolet spectra (in ethanol): max. at 125 m 6 5,850, inflectiontoward 235 to 236 11111., e=4,590;i11fl66 tion toward 247 m e=3,550;max. at 304 my, \e=20,000.

The preceding specific embodiments are illustrative of the process ofthe invention. It is to be understood, however, that other expedientsknown to those skilled in the art can be employed without departing fromthe spirit of the invention or the scope of the appended claims.

We claim:

1. A process for the production of a A gonenic steroid of the formula OR(L l Riv Y 0 wherein R represents a member selected from the groupconsisting of hydrogen and the acyl of an organic carboxylic acid havingfrom 1 to 18 carbon atoms, R represents an alkyl having from 1 to 4carbon atoms, R represents a member selected from the group consistingof lower alkyl, lower alkenyl and lower alkynyl, and B represents amember selected from the group consisting of two hydrogens in the and10B position and a double bond, which comprises (1) reacting a4,5-seco-gonane-5- one of the formula wherein R and R have theabove-assigned meanings, Z is a member selected from the groupconsisting of oxygen,

wherein R" is lower alkyl and R' is selected from the group consistingof lower alkylene and substituted lower alkylene, and A is selected fromthe group consisting of two hydrogens and a double bond, with aketalization agent selected from the group consisting of lower cyclicketals, lower non-cyclic ketals and lower alkanols under ketalizingconditions in the presence of an acid catalyst, (2) saponifying theresultant 3,5 diketals of 4,5-secogonane-3,5-diones of the formula whereX is a member selected from the group consisting of X X/ wherein R, Xand A have the above-assigned meanings by the action of an hydroxyloxidizing agent, (4) reacting the resultant 3,5-diketals of 4,5seco-gonane-3,5,17- triones of the formula 18 wherein R, R, R X and Ahave the above-assigned meanings, (6) hydrolyzing said compounds by theaction of a ketal hydrolyzing agent in the presence of an organicsolvent, (7) subjecting the resulting 17a-R-4,5-seco-gonane- 3,5-dionesof the formula wherein R, R, R and A have the above-assigned meanings tothe action of a cyclizing agent selected from the group consisting ofacid and basic cyclization agents, and (8) recovering said A gonenicsteroid.

2. The process of claim 1 wherein R represents the acyl of an organiccarboxylic acid having from 1 to 18 carbon atoms and R is ethynyl.

3. The process of claim 2 wherein step 4 is conducted with acetylene inthe presence of tertiary alcoholates 0r amides of alkali metals oralkaline earth metals, the recovering of step 5 is conducted byesterifying the corresponding 17/3-hydroxyl compound by the action of anesterifying derivative of an organic carboxylic acid having from 1 to 18carbon atoms under esterifying conditions and said 3,5-diketal of 17a-R-4,5-seco-gonane-3,5- dione is recovered wherein R represents the acylof an organic carboxylic acid having from 1 to 18 carbon atoms, and step7 is conducted by the action of a secondary amine cyclizing agentfollowed by acid hydrolysis of the enamine in the 3 position.

References Cited UNITED STATES PATENTS 3,290,298 12/1966 Joly et a1260-23957 HENRY A. FRENCH, Primary Examiner US. Cl. X.'R.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.5,702,554 Dated Novem r 7, 1972 Inventor( Julien Warnant et a1.

It is certified that errof appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

Col. 1, in the heading,

Priority applications not indicated:

French 'PV 63,086 May 26, 1966,

5 French PV 7u,629 August 30, 1966.

Assignee not indicated:

Roussel'Uclaf k Paris 7, France Col. Line 1 20 In this part of theformula, 8. bond was used instead of a bracket. It should be I. a B

Col. Line 2 12 In this part of the formula, a bond was used instead of abracket. It should be I Col Line 6. 52 "capylic" should be spelledcapgylic Col. L

15 3 4- same" should be sample 0 Signed and Sta-led this twenty-fifth Day Of November 19 75 lSEAH Arrest.- Q

RUT H C. MASON (I. MARSHALL DANN Arresting Officer CommissionerufParenrs and Trademarks FORM PO-IOSO (10-69) USCOMM-DC 603754 69 U 5.GOVERNMENT PRINTING OFFICE: 869. 93 o

